AIDS patients frequently develop central nervous system (CNS) lymphomas, for which there is currently no effective treatment. These AIDS-related CNS lymphomas all carry the Epstein-Barr virus (EBV) genome and express the EBV protein, EBNA 1. The ubiquitous presence of EBV in the AIDS- related CNS lymphomas presents unique opportunities for targeting these malignant cells for destruction using gene therapy approaches. In addition, gene therapy strategies which distinguish between proliferating (tumor) versus nonproliferating (neuronal) cells, and which have already been shown to cure glioblastomas in animal models, may likewise be useful in the treatment of CNS lymphomas. In these studies, we propose to use a recently developed SCID mouse model of CNS lymphoma to develop a variety of gene therapy approaches for the potential treatment of CNS lymphomas in AIDS. In our first specific aim, we will exploit the presence of EBV in AIDS-related CNS lymphomas and insert the "suicide" gene HSV-TK (herpes simplex virus thymidine kinase), which confers ganciclovir sensitivity to cells, into a retroviral vector under the control of the EBV element, oriP. OriP, which contains both an origin of replication and a transcriptional enhancer element, requires the EBV protein EBNA 1 for function. In our second specific aim, we will insert the HSV-TK gene (under the control of the EBNA 1 dependent oriP enhancer element) into a plasmid vector and use the molecular-conjugate method to deliver DNA. The molecular conjugates will include a peptide containing the CD21 ligand (expressed on B cells) to specifically deliver the HSV-TK DNA only to tumor cells. In our third specific aim, we will attempt to induce lytic destruction of the EBV-infected lymphoma cells by using gene therapy to over-express the EBV immediate-early protein, BZLF1. Over-expression of BZLF1 is known to induce lytic EBV infection and consequent lysis of the host cell. In the final specific aim, we will examine the ability of defective HSV mutants to lyse EBV-transformed B cells in vitro, and cure EBV-induced CNS lymphomas in vivo. The studies proposed will not only be important in the development of an animal model system for AIDS-related CNS lymphomas, but should provide critical information regarding which therapeutic approaches are most promising for eventual human trials.